It can be difficult to harvest conditioned media from a suspended cell culture product. In eukaryotic or prokaryotic cultures the total solids can be quite high (e.g., 10%) and the required level of particulate clearance may be to sterilization levels (e.g., not more than 1 micron). The end phase culture can include aggregations of cells and debris that quickly clog prior art filters. Previously, it has been nearly impossible to directly filter more than a small volume of cell culture harvest before the end filter becomes clogged. Typically, researchers have first removed the bulk of cells and cell debris from a cell culture by centrifugation before attempting end filtration. However, this is slow, expensive, and labor intensive. Even with a centrifugation step, filters often become clogged after only a small volume of filtrate has passed through the filter. The researchers must then throw away the first filter and continue the operation with one or more additional filters, until the job is done.
One way to increase the amount of filtrate that can pass through a final filter and to delay clogging is to increase the area of the filter surface. In Meyer et, al., (U.S. Pat. No. 5,232,595), filter surface is increased by arranging a large amount of filter material in a pleated arrangement around a central cavity. Sample fluid flows into the central cavity and is filtered radially, with the filtrate collected on the exterior of the filter in a sealed cartridge. Still the problem of clogging remains. Moreover, there is a tendency for such filters to filter and clog more at the bottom of the filter, particularly at the beginning and end of filtration. The pleated cylinder design presents significant recovery efficiency issues, e.g., in harvesting the final sample volume (trapped at the clogged bottom of the filter, e.g., with the sample pump full of air and no longer able to transfer liquids).
To partially mitigate these problems, most commercially available disposable filter units come with an optional “depth filter” of larger pore size to place in front of the final filter disk. This can help in some cases, but clogging is often only delayed by a small percentage of additional volume, and centrifugation is usually still required for most uses. For example, see Davis et al, (US 2005/0191619) wherein a prefilter of greater pore size is placed in front of the final filter of smaller average pore size. Often, such filter systems clog rapidly with the of bulk cells in the prefilter or with prefiltered sample still clogging the final filter.
In view of the above, a need exists for filter systems that can filter a larger amount of sample before clogging. We believe it would be desirable to have filter designs with smaller residual volumes, e.g., to increase overall sample filtrate recovery. The present invention provides these and other features that will be apparent upon review of the following.